The idea of a “magic bullet” was first proposed by Paul Ehrlich who at the beginning of the 20th century postulated that if a compound could be made that selectively targeted a disease-causing organism or cell, then a toxin for that organism or cell could be delivered along with the agent of selectivity. The discovery of antibodies as specific targeting agents has allowed the actual working of this concept, although the implementation in clinical therapy has required significant modifications.
Therapeutic antibodies have proven effective at fighting cancer, especially in cases where conventional therapy fails: Out of the 21 marketed therapeutic antibodies, 9 are for the treatment of cancer. Even more encouraging is that antibodies for cancer generally operate in a distinct mechanism from traditional chemotherapy or radiotherapy, so they can often be combined with traditional therapies to generate a synergistic effect. However, there is still a lot of room for improvement, in that even the most effective cancer antibodies rarely cure the disease, especially in its more advanced stages.
The first patient treated in the United States with monoclonal antibody therapy was a patient with non-Hodgkin's lymphoma, using a murine monoclonal antibody designated AB 89. Although treatment was not successful in inducing a significant clinical response, it did represent the first proof of principle in humans that a monoclonal antibody could induce transient decreases in the number of circulating tumor cells, induce circulating dead cells, and form complexes with circulating antigen, all with minimal toxicity to the patient. Although there was much excitement about this new treatment modality there were also problems and limitations, including the modulation of antigens off the cell surface and into circulation or internalization.
Monoclonal antibodies achieve their therapeutic effect through various mechanisms. They can have direct effects in producing apoptosis or programmed cell death. They can block growth factor receptors, effectively arresting proliferation of tumor cells. In cells that express monoclonal antibodies, they can bring about anti-idiotype antibody formation. Indirect effects include recruiting cells that have cytotoxicity, such as monocytes and macrophages. This type of antibody-mediated cell kill is called antibody-dependent cell mediated cytotoxicity (ADCC). Monoclonal antibodies also bind complement, leading to direct cell toxicity, known as complement dependent cytotoxicity (CDC).
Rituximab became the first monoclonal antibody approved specifically for cancer therapy, and a number of other naked or immunoconjugated antibodies have followed, including a humanized monoclonal antibody to CD33 conjugated to calicheamicin, and radiolabeled antibodies specific for CD20 (ytrrium-90 ibritumomab tiuxetan and iodine-131 tositumomab).
Rituximab has become the largest-selling biologic drug in clinical oncology, and is active in a variety of human lymphomas and chronic lymphocytic leukemia. This is a chimeric monoclonal antibody targeting the CD20 antigen found on both normal B cells and on most low-grade and some higher grade B-cell lymphomas. It can be effective as a single agent in induction and maintenance therapy. It is primarily used, however, in combination with standard chemotherapies in the treatment of patients with non-Hodgkin's B-cell lymphomas and chronic lymphocytic leukemia.
Alemtuzumab is a humanized monoclonal antibody targeting the CD52 antigen found on B lymphocytes and is used primarily for chronic lymphocytic leukemia, and is effective as induction and maintenance therapy. Alemtuzumab is also reactive with T lymphocytes, and is typically not combined with chemotherapy because of the increased risk of infection. The CD22 antigen is also targeted by a number of antibodies, and has recently demonstrated efficacy combined with toxin in chemotherapy-resistant hairy cell leukemia.
While monoclonal antibodies are now clinically important in the treatment of cancer, particularly leukemias, there remains considerable room for improvement in therapeutic methods. The present invention addresses this need.